Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/64—Cyclic peptides containing only normal peptide links
  • C07K7/645—Cyclosporins; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to novel cyclosporin analogs, processes for preparing them, pharmaceutical compositions containing them, and methods for using these analogs and the compositions containing them for the treatment of medical conditions, including but not limited to ocular conditions such as dry eye.
• Cyclosporins are a class of poly-N-methylated cyclic undecapeptides.
• the first cyclosporin to be isolated was cyclosporin A (CAS Registry Number: 59865-13-3), a naturally occurring fungal metabolite having the following structure:
• Cyclosporin A consists of 11 amino acids and can be further represented as follows:
• MeBmt is (4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine;
• ⁇ Abu is L- ⁇ -aminobutyric acid
• Sar is sarcosine
• MeLeu is N-methyl-L-leucine
• Val is L-valine
• Ala is L-alanine
• DAla is D-alanine
• MeVal is N-methyl-L-valine.
• MeBMT is the amino acid at position 1; sarcosine, the amino acid at position 3.
• the description herein may refer to the amino acid side chain at any one of positions 1-11.
• the carbon to which the amino acid side chain is attached is referred to as the alpha ( ⁇ ) carbon.
• Cyclosporin A is best known for its immunosuppressive properties and is commonly prescribed for use in patients that have undergone bone marrow or organ transplantation.
• the present invention relates to the discovery of water-soluble analogs of cyclosporin A that are potent inhibitors of cyclophilin.
• R 1 is —H, —C 1-6 alkyl, —OC 1-6 alkyl, —CH 2 F, —CH 2 OCH 3 , —SC 1-6 alkyl, —CH 3 , —CH 2 CH 3 , —SCH(CH 3 ) 2 , —CH 2 OH, —SCH 3 , —OCH 3 , —R 13 R 14 ,
• R 2 is —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ;
• R 3 is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ), or —CH 2 CH(R 7 )(CH 2 CH 3 );
• R 4 is —CH 3 , or —CH 2 OH;
• R 5 is —R 8 (CH 2 ) n (C ⁇ O) m —;
• R 6 is —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2 , or —CH 2 CH 2 CH 3 ;
• R 7 is OC 1-5 alkyl;
• R 8 is O, S, CH 2 O, CH 2 S, or CH 2 ;
• R 9 is —H, —C 1-5 alkyl, —C 2-4 flu
• R 10 is —H, —C 1-5 alkyl, —C 2-4 fluoroalkyl, —C 1-5 alkyl-heterocycle, cyanoalkyl,
• R 11 is O, NR 12 , S(O) q , CF 2 , C 1-5 alkylene, CH(OC 1-6 alkyl), divalent C 3-8 cycloalkyl, divalent heterocycle, carbonyl, or taken together with R 9 , R 10 , and the N to which R 9 and R 10 are attached forms a heterocycle
• R 12 is H, CH 3 , or C 1-5 alkyl
• R 13 is O, S, CH 2 O, CH 2 S, CH 2 SO, or CH 2 SO 2
• R 14 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 NH(CH 2 CH
• the invention provides for a compound having Formula I, wherein:
• R 1 is —H, —C 1-6 alkyl, —OC 1-6 alkyl, —CH 2 F, —CH 2 OCH 3 , —SC 1-6 alkyl, —CH 3 , —CH 2 CH 3 , —SCH(CH 3 ) 2 , —CH 2 OH, —SCH 3 , —OCH 3 , —R 13 R 14 ,
• R 2 is —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ;
• R 3 is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ), or —CH 2 CH(R 7 )(CH 2 CH 3 );
• R 4 is —CH 3 , or —CH 2 OH;
• R 5 is —R 8 (CH 2 ) n (C ⁇ O) m —;
• R 6 is —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2 , or —CH 2 CH 2 CH 3 ;
• R 7 is OC 1-5 alkyl;
• R 8 is O, S, CH 2 O, CH 2 S, or CH 2 ;
• R 9 is —H, —C 1-5 alkyl,
• R 10 is —H, —C 1-5 alkyl
• R 11 is O, NR 12 , S(O) q , C 1-5 alkylene, divalent C 3-8 cycloalkyl, divalent heterocycle, carbonyl, or taken together with R 9 , R 10 , and the N to which R 9 and R 10 are attached forms a heterocycle
• R 12 is H, CH 3 , or C 1-5 alkyl
• R 13 is O, S, CH 2 O, CH 2 S, CH 2 SO, or CH 2 SO 2
• R 14 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 NH(CH 2 CH 3 ), heterocycle, or aryl
• n 0,
• a compound having Formula I according to any of the embodiments set forth above may further include the proviso that when R 2 is —CH 3 , and R 3 is —CH 2 CH(CH 3 ) 2 , and R 4 is —CH 3 , and R 6 is —CH 2 CH 3 , then the group
• the invention provides a compound having Formula I, wherein R 1 is not hydrogen (H).
• the invention provides a compound having Formula I, wherein R 6 is —CH 2 CH 3 .
• the invention provides a compound having Formula I, wherein R 6 is —CH(CH 3 )(OH).
• the invention provides a compound having Formula I, wherein R 6 is —CH(CH 3 ) 2 .
• the invention provides a compound having Formula I, wherein R 6 is —CH 2 CH 2 CH 3 .
• the invention provides a compound having Formula I, wherein R 2 is —CH 3 or —CH 2 CH 3 ; R 3 is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , or —CH 2 C(CH 3 ) 2 (OH); R 4 is —CH 3 ; R 6 is —CH 2 CH 3 ; and R 8 is CH 2 .
• the invention provides a compound having Formula I, wherein R 2 is —CH 3 ; R 3 is —CH 2 CH(CH 3 ) 2 ; R 4 is —CH 3 ; R 6 is —CH 2 CH 3 ; and R 8 is CH 2 .
• the invention provides a compound having Formula I, wherein R 1 is —CH 3 , —CH 2 CH 3 , or —SCH 3 ; R 2 is —CH 3 ; R 3 is —CH 2 CH(CH 3 ) 2 ; R 4 is —CH 3 ; R 6 is —CH 2 CH 3 ; and R 8 is CH 2 .
• the invention provides a compound having Formula I, wherein R 2 is —CH 3 , R 3 is —CH 2 CH(CH 3 ) 2 , R 4 is —CH 3 , R 6 is —CH 2 CH 3 , and R 8 is CH 2 .
• the invention provides a compound having Formula I, wherein R 2 is —CH 3 , R 3 is —CH 2 CH(CH 3 ) 2 , R 4 is —CH 3 , R 6 is —CH 2 CH 3 , and R 8 is CH 2 O.
• the invention provides a compound having Formula I, wherein R 2 is —CH 3 , R 3 is —CH 2 CH(CH 3 ) 2 , R 4 is —CH 3 , R 6 is —CH(CH 3 ) 2 , and R 8 is CH 2 .
• the invention provides a compound having Formula I, wherein R 1 is —CH 3 and R 6 is —CH 2 CH 3 .
• the invention provides a compound having Formula I, wherein R 9 is —H, R 10 is
• the invention provides a compound having Formula I, wherein R 9 is —H, R 10 is
• the invention provides a compound having Formula I, wherein R 9 is —H, R 10 is
• R 2 is —CH 3
• R 3 is —CH 2 CH(CH 3 ) 2
• R 4 is —CH 3
• R 6 is —CH 2 CH 3 .
• R 5 is —CH 2 , —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.
• Non-limiting examples of R 11 include O, NCH 3 , NH, SO 2 , S, CH 2 , CF 2 , and CH(OCH 3 ).
• Non-limiting examples of a C 1-6 alkyl-heterocycle include —CH 2 Pyrid-2-yl, —CH 2 Pyrid-3-yl, —CH 2 Pyrimidin-2-yl, —CH 2 Pyrazin-2-yl, —CH 2 -3-Me-Imidazol-4-yl, —CH 2 -2-Me-Pyrazol-3-yl, —CH 2 Pyrid-4-yl, —CH 2 -1-Me-Pyrazol-4-yl, and —CH 2 -1-Me-3-CF 3 -Pyrazol-5-yl.
• a non-limiting example of a cyanoalkyl includes —CH 2 CH(CH 3 )CN.
• R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form a heterocycle.
• the heterocycle is a non-aromatic heterocycle.
• the heterocycle is an aromatic heterocycle.
• the R 9 and R 10 heterocycle, or the heterocycle formed from R 9 , R 10 , and the N to which R 9 and R 10 are attached is independently selected from the group consisting of piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,
• the heterocycle formed by R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together may be optionally substituted by an alkyl, halogen, or haloalkyl.
• a haloalkyl is —CF 3 .
• one or more hydrogen atoms on the heterocycle is replaced with fluorine (F).
• the fluorinated heterocycle is a saturated, non-aromatic heterocycle.
• the fluorinated heterocycle is
• the compound having Formula I is any one of those listed in Tables 1-27. Accordingly, non-limiting examples of a compound according to the present invention include any of the compounds listed in Tables 1-27.
• the present invention also provides for a pharmaceutical composition comprising or consisting of a therapeutically effective amount of a compound having Formula I and a pharmaceutically acceptable excipient.
• Another embodiment is a compound having Formula I, wherein R 1 ⁇ —CH 3 , R 2 ⁇ —CH 3 , R 3 ⁇ —CH 2 CH(CH 3 ) 2 , R 4 ⁇ —CH 3 , R 6 ⁇ —CH 2 CH 3 , R 8 ⁇ CH 2 , R 9 ⁇ —H, R 10 is
• Compounds of the present invention include but are not limited to the following:
• a pharmaceutical composition comprising a compound having Formula I and a pharmaceutically acceptable excipient.
• the excipient can be an ophthalmically acceptable excipient.
• the pharmaceutical composition can be in the form of a liquid, solid, or emulsion.
• the pharmaceutical compositions can be in the form of an aqueous solution.
• a compound of Formula I can be in a purified form.
• the purified form is the form obtained from medium pressure liquid chromatography (MPLC).
• the present invention includes pharmaceutically acceptable salts of any compound having Formula I.
• pharmaceutically acceptable salts refers to salts or complexes that retain the desired biological activity of the compound of Formula I and exhibit minimal or no undesired toxicological effects to the patient, animal, or cell system to which they are administered.
• pharmaceutically acceptable salts according to the invention include therapeutically active non-toxic base or acid salt forms of Formula I.
• the acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or formic acid and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta—Zürich, 2002, 329-3
• the base addition salt form of a compound of Formula I that occurs in its free form as an acid can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-arginine, ethanolamine, betaine, benzathine, morpholine and the like.
• an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like
• an organic base such as for example, L-arginine, ethanolamine, betaine, benzathine, morpholine and the like.
• the present invention further concerns the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition.
• the present invention further encompasses a method for treating a medical condition in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• the medical condition is selected from the group consisting of dry eye, dry eye disease, ocular surface inflammation, blepharitis, meibomian gland disease, allergic conjunctivitis, pterygia, ocular symptoms of graft versus host disease, ocular allergy, atopic keratoconjunctivitis, vernal keratoconjunctivitis, uveitis, anterior uveitis, Behcet's disease, Stevens Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, adenoviral keratoconjunctivitis, ocular rosacea, or pinguecula.
• Another embodiment is a method for reducing corneal transplant rejection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• Another embodiment is a method for reducing inflammation of the eye caused by an ocular surgery, the method comprising administering to the eye(s) of a patient who has received ocular surgery a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• Another embodiment is a method for treating dry eye in a patient in need thereof, the method comprising administering to the eye(s) of the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• Another embodiment is a method for increasing tear production in a patient whose tear production is suppressed or presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, the method comprising administering to the eye(s) of the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• Another embodiment is a method for reducing or preventing an ocular condition in a patient, the method comprising administering a therapeutically effective amount of a compound of Formula I to the patient.
• the ocular condition is selected from the group consisting of dry eye, ocular surface inflammation, blepharitis, meibomian gland disease, allergic conjunctivitis, pterygia, ocular symptoms of graft versus host disease, ocular allergy, atopic keratoconjunctivitis, vernal keratoconjunctivitis, uveitis, anterior uveitis, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, adenoviral keratoconjunctivitis, ocular rosacea, and pinguecula.
• a compound of Formula I may be administered in the form of a pharmaceutical composition, topically, orally, systemically, or by other suitable routes.
• CyP-A potent inhibitors of cyclophilin A
• Cyclosporin A cyclophilin A
• IC50>10 ⁇ M Calcineurin phosphatase assay
• MLR mixed lymphocyte reaction
• IC50 ⁇ 4 ⁇ M Calcineurin phosphatase assay
• MLR mixed lymphocyte reaction
• the present invention includes, but is not limited to, the following embodiments 1-20:
• R 1 is —H, —C 1-6 alkyl, —OC 1-6 alkyl, —CH 2 F, —CH 2 OCH 3 , —SC 1-6 alkyl, —CH 3 , —CH 2 CH 3 , —SCH(CH 3 ) 2 , —CH 2 OH, —SCH 3 , —OCH 3 , —R 13 R 14 ,
• R 2 is —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ;
• R 3 is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ), or —CH 2 CH(R 7 )(CH 2 CH 3 );
• R 4 is —CH 3 or —CH 2 OH;
• R 5 is —R 8 (CH 2 ) n (C ⁇ O) m —;
• R 6 is —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2 , or —CH 2 CH 2 CH 3 ;
• R 7 is OC 1-5 alkyl;
• R 8 is O, S, CH 2 O, CH 2 S, or CH 2 ;
• R 9 is —H, —C 1-5 alkyl,
• R 10 is —H, —C 1-5 alkyl
• R 11 is O, NR 12 , S(O) q , C 1-5 alkylene, divalent C 3-8 cycloalkyl, divalent heterocycle, carbonyl, or taken together with R 9 , R 10 , and the N to which R 9 and R 10 are attached forms a heterocycle
• R 12 is H, CH 3 , or C 1-5 alkyl
• R 13 is O, S, CH 2 O, CH 2 S, CH 2 SO, or CH 2 SO 2
• R 14 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 NH(CH 2 CH 3 ), heterocycle, or aryl
• n 0,
• washing the filter used in step c comprises washing the filter with ethyle acetate.
• a “patient in need in need of treatment” or “patient in need thereof” refers to a human or non-human mammal afflicted with a medical condition, as specified in context.
• a non-human mammal include a horse, pig, monkey, dog, rabbit, guinea pig, rat, or mouse.
• a “therapeutically effective amount” refers to the amount of a compound sufficient to reduce the severity of one or more symptoms associated with, accompanying, or resulting from a medical condition affecting a subject.
• Treating” and “to treat” refers to relieving or reducing at least one symptom associated with or accompanying a medical condition.
• treatment of dry eye and relief of inflammation of the ocular surface may be observed or experienced as an improvement in vision, and/or as a reduction in swelling, pain, redness, dryness, scratchiness, grittiness, foreign body sensation, stinging, burning, or itching. Treating an inflammation of the ocular surface or ocular surface adnexa may improve the visual performance and the optical quality of the eye.
• Improvement in visual performance may include improved optical quality, improved tear film production, secretion, quality, and/or stability, reduced blurring, improved central and/or peripheral field vision, improved visual performance, acuity, or perception, and/or reduced blinking frequency.
• the symptom(s) positively affected by the treatment will depend on the particular condition.
• inflammation refers to the biological response of the living body to injury or other harmful insults. Symptoms of “an inflammation at the ocular surface” can include redness, swelling, heat, pain, and/or loss of function of glands or tissue in the ocular surface or ocular surface adnexa. Other symptoms may include sensations of (and lead a patient to complain of) dryness, burning, itching, or scratchiness. A subject may report a feeling of dust, dirt, sand, or gravel in the eye.
• a “Medical condition” refers to a deviation from or interruption of the normal structure or function of any body part, tissue, organ, or system and that is characterized by an identifiable group of signs or symptoms whose etiology, pathology, and prognosis may be known or unknown.
• a medical condition of a body part, tissue, organ, or system of a human or non-human mammal may result from various causes, including but not limited to injury, surgical trauma, infection, nutritional deficiency, genetic defect, exposure to toxins or radiation, and environmental stress. Medical conditions include ocular conditions such as, for example, inflammation of the ocular surface, and dry eye; and dermatological conditions such as an inflammation of the skin.
• an “ocular condition” is a disease, ailment or condition which affects or involves the eye or one or more parts or regions of the eye.
• Opt surface condition refers to a medical condition that affects or involves one or more parts, regions, or tissues of the ocular surface.
• An ocular surface condition can be an inflammation of an ocular surface tissue, and includes an acute, chronic, and surgically-induced inflammation of an ocular surface tissue.
• optical surface refers to the cornea, the corneal epithelium, the conjunctiva (palpebral, bulbar, and formiceal), the conjunctival blood vessels, Tenon's capsule, the sclera, and the limbus.
• ocular surface adnexa refers to structures in close proximity to the ocular surface, including the lacrimal gland, the eye lids, eyelashes, and eyebrows, the orbital wall, the periocular or extraocular muscles, and the meibomian glands.
• the “eye” is the sense organ for sight, and includes the eyeball, or globe, the orbital sense organ that receives light and transmits visual information to the central nervous system. Broadly speaking the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball.
• the “eye lids” are the structures covering the front of the eye that protect it, limit the amount of light entering the pupil, and help distribute tear film over the exposed corneal surface.
• biocompatible means compatible with living tissue or a living system by not being toxic, injurious, or physiologically reactive and by causing minimal or no immunological reaction.
• alkyl refers to saturated monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 6 carbon atoms.
• One methylene (—CH 2 —) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, amide, sulfonamide, by a divalent C 3-6 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
• Alkyl groups can be independently substituted by halogen, hydroxyl, cycloalkyl, amine groups, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, or sulfonamides groups.
• suitable alkyl groups include methyl (—CH 3 ), ethyl (—CH 2 CH 3 ), n-propyl (—CH 2 CH 2 CH 3 ), isopropyl (—CH(CH 3 ) 2 ), and t-butyl (—C(CH 3 ) 3 ).
• alkylene is a divalent alkyl.
• Non-limiting examples of an alkylene include methylene, ethylene (—CH 2 CH 2 —), and n-propylene (—CH 2 CH 2 CH 2 —).
• cycloalkyl refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon.
• Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, C 3-8 cycloalkyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups or hydroxyl groups.
• cycloalkenyl refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic.
• Cycloalkenyl groups can be independently substituted by halogennitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3-8 cycloalkyl groups or hydroxyl groups.
• halogen refers to an atom of chlorine, bromine, fluorine, iodine.
• haloalkyl refers to an alkyl in which one or more hydrogen atoms on the alkyl have been replaced with a halogen atom.
• a haloalkyl include fluoroalkyls such as —CF 3 and —CH 2 CH 2 CF 3 .
• heterocycle refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, monvalent or divalent, saturated or unsaturated, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure.
• the heterocyclic ring can be interrupted by a C ⁇ O; the S and N heteroatoms can be oxidized.
• Heterocycles can be monocyclic or polycyclic.
• a heterocyle can be bicyclic.
• the rings in a bicyclic or polycyclic heterocycle can be fused or non-fused.
• Heterocyclic ring moieties can be substituted by halogen, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3-8 cycloalkyl groups, or hydroxyl groups.
• alkenyl refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond.
• a C 2-6 alkenyl can be in the E or Z configuration.
• Alkenyl groups can be substituted by C 1-3 alkyl, as defined above, or by halogen.
• alkynyl refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. Alkynyl groups can be substituted by C 1-3 alkyl, as defined above, or by halogen.
• aryl refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen, which can be substituted by halogen, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3-8 cycloalkyl groups or hydroxyl groups.
• a non-limiting example of an aryl is phenyl.
• Preferred substitution site on aryl are the meta and the para positions. Most preferred substitution sites on aryl are the para positions.
• ketone represents an organic compound having a carbonyl group linked to a carbon atom such as —(CO)R x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined herein.
• aldehyde represents a group of formula —C(O)H.
• esters as used herein, represents a group of formula —C(O)OR x , wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined herein.
• hydroxyl as used herein, represents a group of formula —OH.
• carbonyl as used herein, represents a group of formula —C(O)—, which may also be represented as and is equivalent to —(C ⁇ O)—.
• sulfonyl as used herein, represents a group of formula —SO 2 —.
• sulfate represents a group of formula —O—S(O) 2 —O—.
• carboxylic acid as used herein, represents a group of formula —C(O)OH.
• nitro represents a group of formula —NO 2 .
• cyano as used herein, represents a group of formula —CN.
• phosphonic acid as used herein, represents a group of formula —P(O)(OH) 2 .
• phosphoric acid as used herein, represents a group of formula —OP(O)(OH) 2 .
• amide represents a group of formula —C(O)NR x R y , wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle, as defined above.
• amine represents a group of formula —NR x R y , wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
• sulfonamide represents a group of formula —S(O) 2 NR x R y wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
• sulfoxide as used herein, represents a group of formula —S(O)—.
• sulphonic acid represents a group of formula —S(O) 2 OH.
• N represents a nitrogen atom
• morpholinyl as used herein represents a group of formula
• N-methylpiperazinyl as used herein represents a group of formula
• substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound.
• purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
• purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
• any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. And any one or more of these hydrogen atoms can be deuterium.
• protecting groups When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art and in standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1981), Wiley, New York.
• the present invention is directed in part to pharmaceutical compositions comprising a compound having Formula I.
• a pharmaceutical composition comprising a compound of Formula I may be useful for treating dry eye, dry eye disease (i.e., keratoconjunctivitis sicca), ocular surface inflammation (i.e, inflammation of the ocular surface), blepharitis, meibomian gland disease, allergic conjunctivitis, pterygia, ocular symptoms of graft versus host disease, ocular allergy, atopic keratoconjunctivitis, vernal keratoconjunctivitis, uveitis, anterior uveitis, Behcet's disease, Stevens Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, adenoviral keratoconjunctivitis, ocular rosacea, and pinguecula, and to prevent or reduce the risk of corneal transplant rejection in a patient or subject in need thereof. Additionally, one embodiment of
• compositions of the invention may be useful for treating an inflammation of the ocular anterior segment of the eye. More specifically, the pharmaceutical compositions of the invention may be useful for treating an inflammation of the ocular surface or ocular surface adnexa.
• a pharmaceutical composition comprising a compound of Formula I may be useful for reducing one or symptoms associated with an inflammatory dermatological condition.
• an inflammatory dermatological condition that may be subject to treatment is psoriasis.
• a pharmaceutical composition comprising a compound of Formula I may be useful for treating a viral infection. Examples of viral infections may include Hepatitis C infection and Hepatitis B infection.
• one embodiment is a method for reducing one or more or symptoms associated with an inflammatory dermatological condition in a patient in need thereof, comprising administering a pharmaceutical composition comprising a compound of Formula I to the patient.
• Another embodiment is a method for reducing or preventing an inflammatory dermatological condition in a patient, comprising administering a therapeutically effective amount of a compound of Formula I to the patient.
• the method may reduce one or more signs or symptoms of the inflammatory dermatological condition.
• an inflammatory dermatological condition is psoriasis.
• Another embodiment is a method for treating an inflammation of the skin in a patient in need thereof comprising administering a pharmaceutical composition comprising a compound of Formula I to the patient.
• Another embodiment is a method for reducing an inflammation of the skin in a patient, comprising administering a therapeutically effective amount of a compound of Formula I to the patient.
• Another embodiment is a method for treating a viral infection in a patient in need thereof, comprising administering a pharmaceutical composition comprising a compound of Formula I to the patient.
• Another embodiment is a method for reducing one or more signs or symptoms of a viral infection, or for inhibiting the progress of a viral infection in a patient, comprising administering a pharmaceutical composition comprising a compound of Formula I to the patient.
• One embodiment is a method for treating dry eye in a patient in need thereof, comprising administering a pharmaceutical composition comprising a compound of Formula I to the eye(s) of the patient.
• Another embodiment is a method for increasing tear production in a patient whose tear production is suppressed (or presumed to be suppressed) due to ocular inflammation associated with keratoconjunctivitis sicca.
• Another embodiment is a method for reducing ocular surface inflammation in a patient, comprising administering a therapeutically effective amount of a compound having Formula I to the patient.
• the ocular surface inflammation is associated with keratoconjunctivitis sicca.
• the compound having Formula I is administered topically to the patient's eye(s).
• One embodiment is a method for reducing or preventing an ocular condition in a patient, the method comprising administering a therapeutically effective amount of a compound of Formula I to the patient.
• the method may reduce one or more signs or symptoms of the ocular condition.
• “Dry eye” as used herein includes “dry eye disease” as defined by the International Dry Eye Workshop (DEWS) in Lemp et al. (2007) “The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop” Ocul. Surf 5:75-92.
• the International Dry Eye Workshop (DEWS) defines dry eye disease as “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface, accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”
• Dry eye disease is considered to be synonymous with “dry eye syndrome” and “keratoconjunctivitis sicca.” Dry eye disease includes the aqueous deficient (Sjogren and non-Sjogren) and evaporative categories of dry eye disease. An individual with dry eye disease may present with symptoms of both aqueous deficiency (e.g., insufficient tear production) and excessive evaporation of the tear film.
• the pharmaceutical composition can be administered to a patient topically, orally, or systemically (including intravenously or intraarterially). Administration may be to the eye, such as the surface of the eye.
• the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
• the present invention includes methods for treating any of the above ocular conditions in a patient in need thereof by administering a pharmaceutical composition comprising a compound of Formula I to the patient.
• the composition can be administered directly to the ocular surface of the eye or to an ocular region in the eye.
• Modes of direct administration to the eye can include topical delivery and intraocular injection.
• compositions of the invention may also be useful for restoring corneal sensitivity that has been impaired due to surgery on the cornea or other surface of the eye. Impaired corneal sensitivity may also occur after viral infection, such as by HSV-1, HSV-2, and VZV viruses. Patients with impaired corneal sensitivity often complain that their eyes feel dry, even though tear production and evaporation may be normal, suggesting that “dryness” in such patients may actually be a form of corneal neuropathy that results when corneal nerves are severed by surgery or inflamed after viral infection.
• a patient in need of treatment of an “ocular surface inflammation” or more specifically “dry eye” may complain of superficial scratchy pain, abrasiveness, eye dryness, foreign body sensation, scratchiness, ocular discomfort, ocular pain, burning, itching, decreased vision, visual blurriness or cloudiness, irritation or pain from bright light, or decreased visual acuity. Dryness may be experienced and reported as a feeling that moisture is absent, foreign body sensation, and/or as a feeling of dust, sand, or gravel in the eye.
• a patient with dry eye may experience one or more of the following symptoms: stinging and/or burning, dryness, sensation of foreign body (gritty or sandy feeling), itching, sensitivity to light, pain or soreness, intermittent blurred vision, tired or fatigued eyes, and frequent blinking.
• Dry eye may be due to inadequate tear production, a disruption in tear secretion, decreased tear film quality, or excessive evaporation of the tear film at the ocular surface, any and all of which can lead to sensations of dry eye and eye dryness and/or be associated with dry eye disease.
• An individual having dry eye may exhibit one or more of the characteristics or symptoms associated with dry eye disease (keratoconjunctivitis sicca).
• Methods for diagnosing and monitoring dry eye disease may include those described in Bron et al. (2007) “Methodologies to Diagnose and Monitor Dry Eye Disease:Report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007)” Ocul. Surf. 5(2):108-152, and can include, but are not necessarily limited to, symptom questionnaires developed for use in dry eye diagnosis, the fluorescein tear film break up test, ocular surface staining grading with fluorescein/yellow filter, the Schirmer test, and tear osmolarity measurement.
• a common feature of dry eye disease is an unstable tear film due to abnormal or deficient tear production, increased tear evaporation, or imbalance of tear components.
• An unstable tear film may lead to or promote inflammation of the ocular surface (Pflugfelder et al. 2004, Am. J. Ophthalmol. 137:337-342).
• An individual suffering from or in need of treatment of “dry eye,” for the present invention can be one that presents with, is suffering from, or exhibits one or more symptoms of dry eye disease, or ocular surface dryness, or eye dryness, which depending on the individual may include sensations of dry eye (i.e., sensations of eye dryness), tear film instability, decreased tear secretion, delayed clearance, and altered tear composition, or tear hyperosmolarity.
• sensations of dry eye i.e., sensations of eye dryness
• tear film instability i.e., decreased tear secretion, delayed clearance, and altered tear composition, or tear hyperosmolarity.
• dry eye that may potentially be treated with the present pharmaceutical compositions may be chronic or temporary, may occur in one or both eyes of an individual, and in particular patients may be due to or caused by changes in physiological condition; use of contact lenses; allergy to a medication; in response to an external environmental factor such as pollen, dust, particulates, or low humidity; due to a side effect of a medication; aging; low blink rate; vitamin A deficiency; a chemical burn; radiation; blepharitis; rosacea; reaction to the use preservative-containing topical eye drops, such as wetting drops; disorders of the lid aperature; meibomian oil deficiency; lacrimal deficiency; disruption or damage of the lacrimal gland or obstruction of the lacrimal gland duct; reflex block; infection; changes in hormonal balance; eye surgery, including but not limited to refractive laser eye surgery, including LASIK, LASEK, and PRK; or as a result of exposure to an environmental contaminant encountered during
• the dry eye disease may be caused by nutritional disorders or deficiencies (including vitamins), pharmacologic side effects, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and immunodeficient disorders, and may be prevalent in patients who are unable to blink.
• the present invention may be directed to treating dry eye associated with rheumatoid arthritis, lupus erythematosus, polymyositis, rosacea, scleroderma, polyarteritis, thyroiditis, hepatobiliary disease, lymphoma, pulmonary fibrosis, macroglobulinemia, or coeliac disease.
• Blepharitis is a disorder of the meibomian glands, which produce the lipid layer of tear film. With blepharitis, the glands may become inflamed. Symptoms of blepharitis may include eye irritation, soreness, redness and an accumulation of matter on the eyelids. Patients may also experience dry eye as well. Patients suffering from blepharitis may complain of a sandy or itchy feeling of their eyes. There is usually redness, thickening, and irregularity of the lid margins. Accordingly, blepharitis involves an inflammation of the eye lid margins. Blepharitis can also affect the conjunctiva, tear film, and the corneal surface in advanced stages and may be associated with dry eye. Blepharitis is commonly classified into anterior or posterior blepharitis, with anterior affecting the lash bearing region of the lids, and posterior primarily affecting the meibomian gland orifices.
• Meibomian gland disease most often occurs as one of three forms: primary meibomitis, secondary meibomitis, and meibomian seborrhea.
• Meibomian seborrhea is characterized by excessive meibomian secretion in the absence of inflammation (hypersecretory meibomian gland disease).
• Primary meibomitis by contrast, is distinguished by stagnant and inspissated meibomian secretions (obstructive hypersecretory meibomian gland disease).
• Secondary meibomitis represents a localized inflammatory response in which the meibomian glands are secondarily inflamed in a spotty fashion from an anterior lid margin blepharitis.
• Impaired corneal sensitivity often occurs after refractive surgery, such as photorefractive keratectomy, laser assisted sub-epithelium keratomileusis (LASEK), EPI-LASEK, customized transepithelial non-contact ablation, or other procedures in which the corneal nerves are severed. Impaired corneal sensitivity may also occur after viral infection, such as by HSV-1, HSV-2, and VZV viruses. Patients with impaired corneal sensitivity often complain that their eyes feel dry, even though tear production and evaporation may be normal, suggesting that “dryness” in such patients may actually be a form of corneal neuropathy that results when corneal nerves are severed by surgery or inflamed after viral infection.
• Allergic conjunctivitis is an inflammation of the conjunctiva resulting from hypersensitivity to one or more allergens. It may be acute, intermittent, or chronic. It occurs seasonally, that is, at only certain time of the year, or it occurs perennially, that is, chronically throughout the year. Symptoms of seasonal and perennial allergic conjunctivitis include, in addition to inflammation of the conjunctiva, lacrimation, tearing, conjunctival vascular dilation, itching, papillary hyperlasia, chemosis, eyelid edema, and discharge from the eye. The discharge may form a crust over the eyes after a night's sleep.
• Atopic keratoconjunctivitis is a chronic, severe form of allergic conjunctivitis that often leads to visual impairment. Symptoms include itching, burning, pain, redness, foreign body sensation, light sensitivity and blurry vision. There is often a discharge, especially on awakening from a night's sleep; the discharge may be stringy, ropy, and mucoid. The lower conjunctiva is often more prominently affected than the upper conjunctiva. The conjunctiva may range from pale, edematous, and featureless to having the characteristics of advanced disease, including papillary hypertrophy, subepithelial fibrosis, formix foreshortening, trichiasis, entropion, and madurosis.
• the disease progresses to punctate epithelial erosions, corneal neovascularization, and other features of keratopathy which may impair vision.
• CD25+T lymphocytes, macrophages, and dendritic cells are significantly elevated in the substantia intestinal.
• vernal keratoconjunctivitis is a severe form of allergic conjunctivitis, but it tends to affect the upper conjunctiva more prominently than the lower. It occurs in two forms. In the palpebral form, square, hard, flattened, closely packed papillae are present; in the bulbar (limbal) form, the circumcorneal conjunctiva becomes hypertrophied and grayish. Both forms are often accompanied by a mucoid discharge. Corneal epithelium loss may occur, accompanied by pain and photophobia, as may central corneal plaques and Trantas' dots.
• Uveitis the inflammation of the uvea, is responsible for about 10% of the visual impairment in the United States.
• Phacoanaphylactic endophthalmitis is a human autoimmune disease.
• Panuveitis refers to inflammation of the entire uveal (vascular) layer of the eye.
• Posterior uveitis generally refers to chorioentinitis, and anterior uveitis refers to iridocyclitis.
• the inflammatory products i.e. cells, fibrins, excess proteins
• the inflammatory products are commonly found in the fluid spaces if the eye, i.e. anterior chamber, posterior chamber and vitreous space as well as infiltrating the tissue intimately involved in the inflammatory response.
• Uveitis may occur following surgical or traumatic injury to the eye; as a component of an autoimmune disorder, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, and sarcoidosis; as an isolated immune mediated ocular disorder, such as pars planitis, iridocyclitis etc., unassociated with known etiologies; and following certain systemic diseases which cause antibody-antigen complexes to be deposited in the uveal tissues. Together these disorders represent the non-infectious uveitities.
• an autoimmune disorder such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, and sarcoidosis
• an isolated immune mediated ocular disorder such as pars planitis, iridocyclitis etc., unassociated with known etiologies
• systemic diseases which cause antibody-antigen complexes to be deposited in the uveal tissues. Together
• Phacoanaphylaxis is a severe form of uveitis in which the lens in the causative antigen.
• the lens proteins are normally secluded by the lens capsule since before birth. When these proteins are released into the eye by injury or by surgery or occasionally during cataract development, they can become intensely antigenic and incite an autoimmune response. If the response is moderate it is seen as chronic uveitis. If it is very fast in progression the eye becomes seriously inflamed in all segments. This latter response is named phacoanaphylaxis.
• Uveitis is a prominent feature of Behcet's disease, a multi-system inflammatory disorder also characterized by oral and genital ulcers, cutaneous, vascular, joint, and neurological manifestations.
• Rosacea is a chronic and common skin disorder with no identified cause or cure.
• the pathogenesis of rosacea is thought to have multiple factors. Possible factors include exposure to the demodex folliculorum mite, gastrointestinal disease or a vasodilation disorder, and other triggers such as diet or sunlight.
• Patients may present with a variety of symptoms, including inflammatory papules, edema, telangiectasia, rhinophyma and ocular symptoms.
• the ocular signs of rosacea include blepharitis, including anterior blepharitis, conjunctivitis, ulceris, iridocyclitis, keratitis, meibomian gland dysfunction, telangiectasia, erythema, chalazion, hordeolum, interpalpebral hyperemia, conjuctival hyperemia, ciliary base injection, bulbar injection, crusts, sleeves, and superficial punctuate keratopathy.
• blepharitis including anterior blepharitis, conjunctivitis, ulceris, iridocyclitis, keratitis, meibomian gland dysfunction, telangiectasia, erythema, chalazion, hordeolum, interpalpebral hyperemia, conjuctival hyperemia, ciliary base injection, bulbar injection, crusts, sleeves, and superficial punctuate keratopathy.
• the ocular symptoms are nonspecific and may include burning, tearing, decreased tear secretion, redness, and foreign body or gritty or dry sensation, irritation, Itchiness, Blurred vision, Photosensitivity, Watery eyes, bloodshot eyes, Burning, telangiectasia, irregularity of the lid margins, and meibomian gland dysfunction.
• Pinguecula is a benign, yellowish brown proliferative growth that forms on the conjunctiva. Pinguecula may cause irritation and scratchiness of the eye, dry eye, inflammation of the conjunctiva and effect appearance of the eye. Inflamed pinguecula, which cause ocular irritation or become unsightly, may require surgical removal. However, the post-operation scar may be as cosmetically objectionable as the pinguecula and pinguecula regrowth may occur following surgical removal.
• Allogeneic bone marrow transplantation is a well-established treatment for malignant and non-malignant hematological diseases, and is performed in tens of thousands of patients each year.
• Mature donor T cells within the stem cell graft are the main mediators of the beneficial immune effects, but they are also responsible for the induction of graft-versus-host disease (GVHD), the major cause of morbidity and mortality in BMT patients.
• GVHD graft-versus-host disease
• GVHD graft-versus-host disease
• Acute or chronic GVHD occurs within a 100-day period post-BMT that leads to dermatitis, enteritis, and hepatitis.
• Ocular symptoms include blurry vision, foreign body sensation, burning sensation, severe light sensitivity, chronic conjunctivitis, dry eye, and eye pain.
• the present invention includes pharmaceutical compositions comprising, consisting of, or consisting essentially of a compound having Formula I, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.
• a pharmaceutically acceptable excipient may improve the stability or effectiveness of the composition.
• a “pharmaceutically acceptable excipient” is one that is compatible with the compound of Formula I and that is not harmful to the person receiving the pharmaceutical composition. Mixtures of two or more of such suitable excipients may be used.
• a pharmaceutical composition may comprise two or more compounds having Formula I, or two or more salts thereof.
• compositions of the present invention can be in the form of a liquid (such as an aqueous solution), solid, gel, or emulsion.
• the composition can be sterilized and therefore prepared in sterile form for pharmaceutical use.
• the pharmaceutical composition may be prepared in a unit dosage form suitable for oral, systemic (arterial or intravenous), or topical administration to a patient.
• the pharmaceutical composition may be prepared in an aqueous liquid or emulsion form suitable or acceptable for administration or topical application to the eye(s) of the patient.
• compositions may be prepared by combining a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient, with one or more pharmaceutically acceptable excipients.
• the excipient is further preferably ophthalmically acceptable, that is, is causes little or no injury to the eye.
• a therapeutically effective amount of a compound of Formula I can be from about 0.001% (w/v) to about 5% (w/v), from about 0.001% (w/v) to about 1.0% (w/v), from about 0.01% (w/v) to about 0.5% (w/v), from about 0.01% to about 1% (w/v), from about 0.1% to about 0.5% (w/v), or from about 0.5% to about 1% (w/v) in liquid and emulsion formulations.
• the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated.
• Emulsions may be prepared by combining a compound of Formula I in a sterile lipophilic vehicle or fixed oil.
• the lipophilic vehicle or fixed oil may be selected from the group consisting of synthetic mono- and diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils, sesame oil, coconut oil, peanut oil, cottonseed oil, castor oil, olive oil, mineral oil, synthetic fatty vehicles, and ethyl oleate. Buffers, emulsifiers, dispersing agents, preservatives, antioxidants, and the like can be incorporated as required.
• compositions for use with the invention may include but are not limited to preservatives, buffering agents, antioxidants, lipophilic vehicles, hydrophilic vehicles, tonicity agents, electrolytes, thickeners, neutralizing agents, emulsifiers, dispersing agents, demulcents, plasticizers, occlusive agents, and film formers, and combinations thereof.
• Certain compositions may include both a buffer component and a tonicity component.
• Useful preservatives may include benzalkonium chloride, PURITE®, sodium bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, methyl and ethyl parabens, methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol, hexetidine, chlorite components, such as stabilized chlorine dioxide, metal chlorite, and other ophthalmically acceptable preservatives.
• concentration of the preservative component, if any, in the present compositions is a concentration effective to preserve the composition, and is often in a range of about 0.00001% to about 0.05% or about 0.1% (w/w) of the composition.
• Acceptable buffering agents may include HEPES and those prepared from a suitable combination of the acid and/or base forms of acetates, citrates, phosphates, carbonates, succinates, and borates, such as sodium citrate dihydrate and boric acid.
• Phosphate buffers may be composed of sodium phosphate dibasic and sodium phosphate monobasic. Examples include monosodium phosphate, monohydrate, sodium phosphate dibasic heptahydrate, and sodium phosphate monobasic monohydrate.
• Buffering agents may be provided in any of the compositions in an amount effective to control the pH of the composition.
• the pH of the composition can be in a range of about 6 to about 8, about 7 to about 8, about 7 to about 7.6, or about 7.5 to about 8.
• Useful tonicity agents may include glycerin, sugar alcohols, xylitol, sorbitol, glycerol, erythritol, mannitol, salts, potassium chloride and/or sodium chloride.
• Tonicity agents may be provided in an amount effective to control the tonicity or osmolality of the compositions.
• the osmolality of the composition can be in a range of about 200 to about 400, or about 250 to about 350, mOsmol/kg respectively.
• the composition is isotonic.
• An isotonic solution is a solution that has the same solute concentration as that inside normal cells of the body and the blood.
• Useful lipophilic vehicles may include castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic/capric triglycerides, cetyl alcohols, and stearyl alcohols.
• Useful hydrophilic vehicles include water.
• a pharmaceutical composition may optionally comprise an acceptable amount of dimethyl sulfoxide as an excipient. Additional examples of excipients that may be optionally included in the pharmaceutical compositions of the present invention may include those listed in Table A.
• the present invention includes processes (i.e., methods) for preparing compounds having Formula I.
• Compounds having Formula I may be prepared according to the following reaction schemes and accompanying discussions. Unless otherwise indicated, the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , and R 14 , and m, n, p, and q variables; and structure of Formula I; in the following reaction schemes and discussion are as defined above in the Summary of the Invention.
• the present invention includes isotopically-labeled compounds of Formula I.
• a compound having Formula I may contain one or more isotopic atoms such as deuterium 2 H (or D) in place of proton 1 H (or H) or 13 C in place of 12 C and the like. Similar substitutions can be employed for N, O and S.
• isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention.
• These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
• Isotopically-labeled compounds of the present invention are identical to those recited herein, except that one or more atoms in the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl and 123 I, respectively.
• the present invention can further include the Intermediates formed by the following schemes.
• cyclosporin A (CAS Number 59865-13-3).
• Cyclosporin A may be obtained commercially from suppliers such as Sigma-Aldrich (St. Louis, Mo., United States) or TCI America (Portland, Oreg., United States).
• Other cyclosporin starting materials such as Cyclosporin D (CAS Registry Number 63775-96-2) may also be obtained through commercial suppliers such as Enzo Life Sciences (Ann Arbor, Mich., United States; Farmingdale, N.Y., United States).
• Cyclosporin starting materials may be prepared from cyclosporin A as described by M. Mutter et al. Tet. Lett. 2000, 41, 7193-7196 and U.S. Pat. No. 5,214,130.
• characterization of the compounds is performed according to the following methods: Proton nuclear magnetic resonance ( 1 H NMR, written occasionally as 1 H NMR) and carbon nuclear magnetic resonance ( 13 C NMR, written occasionally as 13 C NMR) spectra were recorded on a Bruker 300 or 500 MHz spectrometer in deuterated solvent. Chemical shifts were reported as ⁇ (delta) values in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm) and multiplicities were reported as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; dd, doublet of doublets; and bt, broad triplet. Data were reported in the following format: chemical shift (multiplicity, integrated intensity, assignment).
• Electron spray mass spectra were recorded on a Micromass ZQ.
• Intermediate 16 By substituting chloroethylchloroformate for chloromethylchloroformate (reactant 3 in Preparation of Intermediate 1), Intermediate 16 can be produced (structure shown below). Intermediates 4 and 16 can serve as the starting material for the production of amines and amides of Formula I, as shown and described below.
• Scheme I shows morpholine as the reactant at Step 4
• Intermediate 4 can be reacted with other heterocycles or amines to produce a set of corresponding intermediates.
• Each of the resulting intermediates can then be separately deprotected according to Step 5 of Scheme I to produce a compound of Formula I.
• the distance between the amine in the side chain at position 1 and the cyclosporin scaffold can be varied (that is, the value of n can be adjusted between 0 and 4) according to the schemes set forth herein.
• reaction mixture was cooled to room temperature then purified by silicagel chromatography using a solvent gradient of 100% dichloromethane ⁇ 96% dichloromethane/4% methanol to provide [(3E,6R,7R,8S)-1-bromo-7-hydroxy-6-methyl-8-(methylamino)-non-3-enoic acid] 1 cyclosporin A (Intermediate 6) as an off-white solid.
• Grubbs' catalyst second generation (Grubbs II catalyst) is described in U.S. Patent Application Publication No. 2003/0186855. Longer chain brominated alkenes may be used at Step 1 if desired to produce a longer side chain at position 1.
• Schemes III and IV describe efficient processes for the synthesis of amides of Formula I.
• Scheme III describes the use of metathesis using Grubbs II catalyst while Scheme IV describes the use of Wittig chemistry.
• the metathesis route (scheme III) is two steps shorter than the Wittig route (scheme IV) starting from intermediate 1.
• reaction mixture was cooled to room temperature then purified by silicagel chromatography using a solvent gradient of 100% dichloromethane ⁇ 96% dichloromethane/4% methanol to provide [[2E,5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-oct-2-enedioic acid]methyl ester] 1 [methylene-Sar] 3 cyclosporin A (Intermediate 7) as an off-white solid.
• reaction mixture was stirred at room temperature for 17 hours, then additional dry acetone (2 mL) and bis(acetonitrile)dichloropalladium (II) (1 mg, 0.004 mmol) were added and the reaction mixture was stirred for a further 3 days.
• the reaction mixture was filtered through celite using diethyl ether and methanol as solvents.
• reaction mixture was filtered through celite then concentrated in vacuo to provide the dihydro version of intermediate 11 [[(5R,6R,7S)-6-(t-butyldimethylsilanyloxy)-5-methyl-7-(methylamino)-octanedioic acid]1[(R)-methyl-Sar]3 cyclosporin A (Intermediate 56) as a white solid.
• Intermediate 53 was prepared by reduction of the aldehyde, Intermediate 4, using sodium borohydride in a solvent such as methanol, as described in US 2004/0110666.
• Step 2 in Scheme VIII above was carried out in an identical manner as described in step 2 Scheme 1 to give intermediate 16.
• Intermediate 16 may be substituted for Intermediate 1 in any of the schemes shown above to obtain compounds of Formula I in which R 1 is ethyl.
• Alternative compounds of Formula I may be produced according to Scheme VIII through the use of alternative heterocycles or amines at Step 3 in Scheme VIII.
• Exemplary compounds that may be used in place of morpholine at step 3 in scheme VIII to produce compounds of the present invention include but are not limited to 2 methyloctahydropyrrolo[3,4c]pyrrole, piperidine, N-methyl piperazine, homomorpholine, and pyrrolidine.
• H-cube is a continuous flow reactor for carrying out hydrogenation under pressure.
• the hydrogenation is carried out using palladium on carbon catalyst at a hydrogen pressure of 30 atmospheres.
• reaction mixture was stirred for a further 2 hours before methyl disulphide (0.42 ml, 4.75 mmol) was added and the reaction was allowed to warm to room temperature over 18 h. After this time the reaction mixture was quenched with ammonium hydroxide solution (100 ml) then extracted with ethyl acetate (2 ⁇ 50 ml). The combined organic phases were washed with saturated brine (100 ml), then dried (MgSO 4 ), filtered and evaporated.
• the crude orange solid obtained (0.4 g) was purified by passing through a 20 g silica column using 3% MeOH/dichloromethane as the eluent to obtain Compound K ([(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(S)-thiomethyl-Sar] 3 cyclosporin A) as an off white solid.
• Intermediate 18 is a structural variant of cyclosporin A having an —OCH 3 at the position 3 ⁇ -carbon. Intermediate 18 can be used in place of cyclosporin A according to any of the schemes shown herein to produce compounds of Formula I (e.g., amines and amides of Formula I) in which R 1 is —OCH 3 . Intermediate 18 can be prepared as described in Example 1 ((3-methoxycyclosporin) of US 2010/0167996. The chemical structure of Intermediate 18 is shown below.
• Compound B can be prepared from Intermediate 18 as shown below
• Intermediate 23 is a structural variant of cyclosporine A having a —CH 2 OCH 3 at the position 3 ⁇ -carbon.
• Intermediate 23 can be used in place of Cyclosporin A according to any of the schemes shown herein to produce compounds of Formula I (e.g., amines and amides of Formula I) in which R 1 is —CH 2 OCH 3 .
• the synthetic scheme for preparing Intermediate 23 is shown below.
• [(D)-Serine] 3 cyclosporin A is prepared as described by D. Seebach et al. (1993) Helvetica Chimica Acta 73(4): 1564-1590.
• reaction mixture was diluted with water (5 mL) and dichloromethane (5 mL) and the layers separated. The aqueous layer was further extracted with dichloromethane (3 ⁇ 10 mL) and the combined organic layers dried (MgSO 4 ) and evaporated in vacuo. The residue was purified by silicagel chromatography using 6% methanol in dichloromethane to provide [(R)-methoxymethylene-Sar] 3 cyclosporin A (Intermediate 23) as an off-white solid.
• Compound D can be prepared from Intermediate 23 and similarly Compounds V, S and AD can be prepared from [(D)-Serine] 3 cyclosporin A as shown below.
• Compound EO and Compound EP can be prepared from [D-Serine] 3 cyclosporin A using 2,2,6,6-tetrafluoromorpholine or 3,3-difluoropyrrolidine as reagents.
• Scheme X describes the acylation of Intermediate 1 (Step 1) and bromination of Intermediate 29 by N-bromosuccinimide azobisisobutyrylnitrile in carbon tetrachloride (Step 2) carried out as described by M K Eberle et al. J. Org. Chem. 1992, 57, 2689-2691. Steps 3 and 4 are carried out as described in Steps 2 and 3 in Scheme II. Intermediate 1 is obtained as described in Scheme I. Step 5 is carried out by stirring Intermediate 32 in a solution of potassium carbonate in a mixture of methanol and water as described for Example 8 in US 2003/0212249.
• Scheme Xa describes the use of Wittig chemistry on Intermediate 4 (Step 1).
• Intermediate 4 is obtained as described in Scheme I.
• Deprotection of Intermediate 35 and hydrogenation of Intermediate 36 are carried out as described in Steps 5 and 3, respectively, in Scheme I.
• Exemplary syntheses according to Scheme Xa are described below for the preparation of Compounds KF and KG.
• thiols such as morpholinoethylthiol, diethylaminopropylthiol, ethanethiol and morpholinopropylthiol may be reacted with Intermediate 34 in a similar manner to give the corresponding compounds of Formula I.
• Compound DA is prepared from intermediate 4 according to Scheme I and the steps shown below.
• Compounds DB, DC, DD, DE, DF, DG, DH, DI, DJ, DK, DL, DM, DN, DO, DP, DQ, and DR are prepared in a similar manner according to Scheme I.
• the structures for each of these compounds along with their corresponding proton NMR and electron spray mass spectroscopy data are given below.
• Compound EI is prepared from an intermediate similar to intermediate 15 by using Scheme Xa in a manner similar to that used to prepare Compound KG, as shown below.
• Intermediate 101 is prepared from CsA in a manner similar to that used to prepare intermediate 15 in Scheme VI, as shown by the scheme shown below.
• Intermediate 104 is prepared in a similar manner to intermediate 2 in Scheme I.
• Intermediate 105 is prepared in a similar manner to intermediate 3 in Scheme I.
• Intermediate 106 is prepared in a similar manner to intermediate 14 in Scheme VI.
• Example Compounds of Formula I are listed and described in Tables 1-27, below.
• Compounds of the present invention include those listed and described in Tables 1-27, below, and their pharmaceutically acceptable salts.
• Cyclophilin A (Cyp A) Inhibitory Activity, immunosuppressive Potential, and aqueous solubility for select Compounds having Formula I are described in Tables 28-35. General procedures and assays used to obtain the data are given below.
• the protease-free PPIase assay measures the rate of cis to trans conversion of a peptide substrate catalyzed by the enzyme cyclophilin A.
• Addition of a cyclophilin A inhibitor e.g., a test compound
• a K i value of less than 10 nM demonstrates that the test compound is a potent inhibitor of cyclophilin A.
• Succinimide-Ala-Ala-Pro-Phe-p-nitroanilide nitroanailide (SUC-AAPF-pNA) (from Bachem AG, L-1400), 20 mg/ml prepared in 0.5 M LiC1 in trifluoroethanol.
• a first order rate equation was fitted to the absorbance data, for each concentration of inhibitor, to obtain the rate constant (the first 10 to 15 seconds were excluded as mixing causes errors in this portion of curve).
• the catalytic rate was calculated from the enzymatic rate constant minus the background rate constant.
• An exponential curve was generated using the catalytic rate constants versus the inhibitor concentration to obtain the K i value for the inhibitor.
• the K i value is indicative of the binding affinity between the test compound and cyclophilin A.
• the calcineurin phosphatase assay is a means for estimating the immunosuppressive potential of a test compound.
• Calcineurin is a serine-threonine protein phosphatase that on activation dephosphorylates members of the nuclear factor of activated T cells (NFAT), which are important in T lymphocyte activation.
• Cyclosporin A (CsA) bound to cyclophilin A (Cyp A) inhibits calcineurin activity, thus resulting in immunosuppressive effects.
• CsA only inhibits calcineurin when bound to Cyp A
• some Cyclosporin A (CsA) analogs will also bind calcineurin in the absence of Cyp A.
• some CsA analogs bind cyclophilin A but do not inhibit calcineurin activity.
• the CaN assay kit used is based on a colorimetric assay for measuring calcineurin phosphatase activity, and it is commercially available (Enzo Life Sciences and Calbiochem). Calmodulin is also required for calcineurin activity and RII phosphopeptide is used as an efficient peptide substrate for calcineurin.
• inhibitor compounds were diluted in UPW in polypropylene low-binding 96 well plates at 5 ⁇ the final assay concentration.
• a 4-point dilution series of the inhibitor was prepared in duplicate to obtain a final assay concentration of 10, 1, 0.1 and 0.01 ⁇ M.
• a 7-point dilution series was prepared to obtain a 1:1 complex of the inhibitor with CypA; the inhibitor and Cyp A final assay concentrations of 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014 ⁇ M were prepared.
• Cs A inhibitor controls were also prepared to obtain a final concentration of 10 ⁇ M Cs A with and without 10 ⁇ M Cyp A.
• the reaction was allowed to proceed at 30° C. for a time period in which the reaction is linear for about 60 minutes.
• the reaction was then terminated by adding 100 ⁇ l of the Malachite Green reagent.
• the color was allowed to develop for 15-30 minutes at room temperature before the absorbance at 620 nm was measured using a plate reader (Molecular Devices—SpectraMax M5).
• the data were analyzed by subtracting ‘no Calcineurin blank’ from all the absorbance readings and plotting the background corrected absorbances against Log 10 inhibitor concentration.
• a sigmoidal-dose response curve was fitted to the data using GraphPad Prism Software.
• Cyclosporin A is a potent inhibitor of calcineurin activity and therefore a potent immunosuppressive. It exerts its immunosuppressive activity by binding to cyclophilin A to form a complex, which then binds to calcineurin and thereby inhibits calcineurin activity. As shown in the tables, Cyclosporin A has a IC 50 value of 210 nM in the calcineurin/cyclophilin A assay. Thus, compounds with values higher than 210 nM in this assay will be predictably less immunosuppressive than cyclosporin A.
• the MLR assay is widely used in the field of immunology to measure T cell proliferation, and therefore is another means of estimating the immunosuppressive potential of test compounds.
• Stimulator e.g. BALB/c mice
• Responder e.g. C57BL/6 mice
• Alloimmunity results in robust proliferation of T cells contained within the splenocyte cell population from both strains of mice.
• the Stimulator cells (BALB/c) are first inactivated via x-irradiation before co-culture with Responder cells in the absence or presence of different concentrations of test compound. If the test compound present in the culture medium is immunosuppressive the proliferation of the responder cells is reduced. Total proliferation is quantified by the cellular uptake of [ 3 H]-thymidine, which occurs during cell division. Therefore, compounds that are less immunosuppressive than CsA will require a higher concentration to reduce T cell proliferation; and compounds that are not immunosuppressive will not affect T cell proliferation even at the highest concentrations tested.
• mice Female C57BL/6 and BALB/c mice, 6-8 weeks of age, were obtained from the Frederick Cancer Research and Development Center of the National Cancer Institute (Frederick, Md.). Spleens were harvested aseptically from all mice and single cell suspensions were prepared by disaggregating the cells with frosted glass slides, allowing the debris to settle, and washing the cells twice with complete medium.
• Complete medium consists of RPMI 1640 medium containing 25 mM HEPES buffer (HyClone, Logan, Utah) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Atlanta Biologicals, Lawrenceville, Ga.), 100 ⁇ g/mL streptomycin, 100 U/mL penicillin G, 0.25 ⁇ g/mL amphotericin B (HyClone), 2 mM L-glutamine dipeptide (HyClone), and 2 ⁇ 10 ⁇ 5 M 2-mercaptoethanol (Sigma). Cells were washed twice and resuspended in complete medium. Cell counts were performed using a Beckman Coulter Z-1 particle counter (Fullerton, Calif.). Cell viability was determined by propidium iodide (PI) staining using an Accuri C6 flow cytometer (Ann Arbor, Mich.).
• PI propidium iodide
• Spleen cells from C57BL/6 (H-2 b ) and BALB/c (H-2 d ) were used as responder (R) and stimulator (S) cells, respectively.
• Cells were plated in triplicate in 96-well flat microtiter plates (Costar, Cambridge, Mass.) such that each well contained 2 ⁇ 10 5 R and 8 ⁇ 10 5 S cells. Cultures were incubated in the absence or presence of various concentrations of CsA, test compounds (e.g., a compound of Formula I), or medium at 37° C.
• the aqueous solubility of a compound of Formula I in buffer was measured by recording the onset of precipitation of the compound as a function of increasing concentration. The onset of precipitation, if it occurred, was detected by an increase in absorbance at 650 nm.
• Assay buffer 247.5 ⁇ l was placed into flat bottomed transparent 96-well plate.
• DMSO 2.5 ⁇ l was added.
• test and control samples 2.5 ⁇ l of the appropriate DMSO dilution stocks were added to the appropriate well. All test and control compounds were performed in triplicate.
• the plates were sealed with adhesive plate seal and shaken at 250 rpm at 25° C. for 18 h on a plate shaker.
• R 9 , R 10 , and R 11 R 12 n m p q F —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — A —H R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 —
• R 9 , R 10 , and R 11 R 12 n m p q L —CH 3 R 11 is NR 12 ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 CH 3 0 0 1 — LL —H R 11 is NR 12 ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 CH 3 0 0 1 —
• R 9 , R 10 , and R 11 R 12 n m p q N —CH 3 R 11 is NR 12 ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 H 0 0 1 — NN —H R 11 is NR 12 ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 H 0 0 1 —
• R 9 , R 10 , and R 11 R 12 n m p q B —OCH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — C —H R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 3 0 1 —
• R 9 , R 10 , and R 11 R 12 n m p q H —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 1 1 1 — E —H R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 1 1 1 —
• R 9 , R 10 , and R 11 R 12 n m p q AB —CH 2 CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — Z —CH 3 R 11 is S(O) q ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 1 1 1 2
• R 1 R 9 , R 10 , and R 11 R 12 n m p q P —CH 3 R 11 is S(O) q ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 2 Q —CH 3 R 11 is CH 2 ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 1 1 1 —
• R 1 R 9 , R 10 , and R 11 R 12 n m p q AC R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — S R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 —
• Compound R 1 R 9 , R 10 , and R 11 R 12 n m p q AD R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 —
• Compound R 1 R 9 , R 10 , and R 11 R 12 n m p q K —SCH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 —
• R 9 , R 10 , and R 11 R 12 n m p q DS —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — DT —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — DU —CH 3 R 11 is N; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 —
• R 9 , R 10 , and R 11 R 12 n m p q DV —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — DW —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — DX —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 —
• R 9 , R 10 , and R 11 R 12 n m p q EB —CH 3 R 11 is CH 2 ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — EC —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — ED —CH 3 R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — EE —CH 3 R 11 is N; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein
• R 9 , R 10 , and R 11 R 12 n m p q EG —CH 3 R 11 is NR 12 ; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 CH 3 0 0 1 — EH —CH 3 R 11 is CH 2 (OCH 3 ); and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 0 0 1 — EI —H R 11 is O; and R 9 , R 10 , R 11 , and the N to which R 9 and R 10 are attached taken together form: wherein “*” represents the point of attachment to R 5 — 1 0 1 —
• Cyclophilin A (Cyp A) Inhibitory Activity, immunosuppressive potential, and aqueous solubility for select Compounds having Formula I Protease- Calcineurin Mixed free Phosphatase Lymphocyte Water PPIase (CaN) Reaction Solubility Assay* Assay (+CypA)** (MLR) Assay**** Compound K i (nM) IC 50 (nM) Assay*** ( ⁇ M) Cyclo- 1.5 210 1 10-25 sporin A F 4.5 >10,000 144 >100 A 23 >10,000 >100 L 7.3 >10,000 541 >100 LL 46 >10,000 N 6.1 >10,000 ⁇ 100 NN 120 >10,000 B 8 >10,000 >100 G 6.2 >10,000 77 >100 C 14 >10,000 84 >100 M 90 75-100 D 10 >10,000 >1000 75-100 H 3.9 >10,000 418 >100
• Cyclophilin A Inhibitory Activity, immunosuppressive potential, and aqueous solubility for select Compounds having Formula I Protease- Calcineurin Mixed free Phosphatase Lymphocyte Water PPIase (CaN) Reaction Solubility Assay* Assay (+CypA)** (MLR) Assay**** Compound K i (nM) IC 50 (nM) Assay*** ( ⁇ M) T 5 >10,000 >100 U 4 >10,000 75-100 ZY 5.7 >10,000 75-100 K 4.9 >10,000 >1000 >100 AB 5.6 >10,000 >100 Y 4.1 >10,000 >1000 >100 AK 42 >10,000 W 1.9 >10,000 >100 Z 2 >10,000 >100 ZZ 2.6 >10,000 >100 E 24 >10,000
• Cyclophilin A Inhibitory Activity, immunosuppressive potential, and aqueous solubility for select Compounds having Formula I Protease- Calcineurin Mixed free Phosphatase Lymphocyte Water PPIase (CaN) Reaction Solubility Assay* Assay (+CypA)** (MLR) Assay**** Compound K i (nM) IC 50 (nM) Assay*** ( ⁇ M) O 8.2 >10,000 >1000 >100 AF 28 >100 AG 18 >100 I 7.7 >10,000 >1000 25-50 AH 4.7 >10,000 >100
• Cyclophilin A Inhibitory Activity, immunosuppressive potential, and aqueous solubility for select Compounds having Formula I Protease- Calcineurin Mixed free Phosphatase Lymphocyte Water PPIase (CaN) Reaction Solubility Assay* Assay (+CypA)** (MLR) Assay**** Compound K i (nM) IC 50 (nM) Assay*** ( ⁇ M) AI 3.3 >10,000 >100 AJ 12 50-75 J 3.7 6,300 50-75 P 3.2 >10,000 >100 Q 3.5 >10,000 50-75 ZX 2.3 >10,000 >100
• Cyclophilin A Inhibitory Activity, immunosuppressive potential, and aqueous solubility for select Compounds having Formula I Protease- Calcineurin Mixed free Phosphatase Lymphocyte Water PPIase (CaN) Reaction Solubility Assay* Assay (+CypA)** (MLR) Assay**** Compound K i (nM) IC 50 (nM) Assay*** ( ⁇ M) AC 7.5 >10,000 >100 S 10 >10,000 >100 V 4.5 >10,000 >100 X 4.9 >10,000 >100 AD 18 >10,000 AL 27 >10,000 >100 AN 15 >10,000 AM 1.9 >8,900 25-50 KF 7.8 >10,000 KG 3.8 >10,000
• Cyclophilin A Inhibitory Activity, immunosuppressive potential, and aqueous solubility for select Compounds having Formula I Protease- Calcineurin Mixed free Phosphatase Lymphocyte Water PPIase (CaN) Reaction Solubility Assay* Assay (+CypA)** (MLR) Assay**** Compound K i (nM) IC 50 (nM) Assay*** ( ⁇ M) DA 4.9 >10,000 75-100 DB 7.4 >10,000 75-100 DC 6.0 >10,000 10-25 DD 4.8 >10,000 25-50 DE 5.8 >10,000 >100 DF 14 >10,000 >100 DG 8.5 >10,000 >100 DH 9.1 >10,000 >100 DI 4.3 >10,000 >100 DJ 5.4 >10,000 >100 DK 13 6,300 >100 DL 5.7 >10,000 >100 DM 23 DN 5.5 >10,000 25-50 DO 2.8 >10,000 10-25 DP 16.2 >10,000 DQ 11 >10,000 DR 8.4 >10,000 DQ 11 >10,000 DR 8.4 >10,000 DQ 11 >10,000
• Cyclophilin A Inhibitory Activity, immunosuppressive potential, and aqueous solubility for select Compounds having Formula I Protease- Calcineurin Mixed free Phosphatase Lymphocyte Water PPIase (CaN) Reaction Solubility Assay* Assay (+CypA)** (MLR) Assay**** Compound K i (nM) IC 50 (nM) Assay*** ( ⁇ M) DS 12 >10,000 75-100 DT 4.7 >10,000 >100 DU 9.2 >10,000 >100 DV 4.3 >10,000 250 50-75 DW 6.5 >10,000 >100 DX 5.2 7,600 250 25-50 DY 13 >10,000 >100 DZ 6.0 >10,000 25-50 EA 22 >10,000 EF 40 >10,000 EB 3.7 >10,000 EC 5.2 >10,000 ED 3.8 >10,000 EE 9.1 >10,000

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